Toward subtask-decomposition-based learning and benchmarking for predicting genetic perturbation outcomes and beyond

Deciphering cellular responses to genetic perturbations is fundamental for a wide array of biomedical applications. However, there are three main challenges: predicting single-genetic-perturbation outcomes, predicting multiple-genetic-perturbation outcomes and predicting genetic outcomes across cell lines. Here we introduce Subtask Decomposition Modeling for Genetic Perturbation Prediction (STAMP), a flexible artificial intelligence strategy for genetic perturbation outcome prediction and downstream applications. STAMP formulates genetic perturbation prediction as a subtask decomposition problem by resolving three progressive subtasks in a problem decomposition manner, that is, identifying postperturbation differentially expressed genes, determining the expression change directions of differentially expressed genes and finally estimating the magnitudes of gene expression changes. STAMP exhibits a substantial improvement over the existing approaches on three subtasks and beyond, including the ability to identify key regulatory genes and pathways on small samples and to reveal precise genetic interactions of diverse types. By employing the subtask decomposition strategy, STAMP outperforms existing models in single, multiple and cross-cell-line scenarios for genetic perturbation prediction, showing potential to uncover gene regulations and interactions.